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Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.

ABSTRACT: Dynamic and disordered regions in native proteins are often critical for their function, particularly in ligand binding and signaling. In certain proteins, however, such regions can contribute to misfolding and pathologic deposition as amyloid fibrils in vivo. For example, dynamic and disordered regions can promote amyloid formation by destabilizing the native structure, by directly triggering the aggregation, by promoting protein condensation, or by acting as sites of early proteolytic cleavage that favor a release of aggregation-prone fragments or facilitate fibril maturation. At the same time, enhanced dynamics in the native protein state accelerates proteolytic degradation that counteracts amyloid accumulation in vivo. Therefore, the functional need for dynamic protein regions must be balanced against their inherently labile nature. How exactly this balance is achieved and how is it shifted upon amyloidogenic mutations or post-translational modifications? To illustrate possible scenarios, here we review the beneficial and pathologic roles of dynamic and disordered regions in the native states of three families of human plasma proteins that form amyloid precursors in systemic amyloidoses: immunoglobulin light chain, apolipoproteins, and serum amyloid A. Analysis of structure, stability and local dynamics of these diverse proteins and their amyloidogenic variants exemplifies how disordered/dynamic regions can provide a functional advantage as well as an Achilles heel in pathologic amyloid formation.

SUBMITTER: Lewkowicz E

PROVIDER: S-EPMC9416430 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.

Lewkowicz Emily E Gursky Olga O

Biophysical chemistry 20211014

Dynamic and disordered regions in native proteins are often critical for their function, particularly in ligand binding and signaling. In certain proteins, however, such regions can contribute to misfolding and pathologic deposition as amyloid fibrils in vivo. For example, dynamic and disordered regions can promote amyloid formation by destabilizing the native structure, by directly triggering the aggregation, by promoting protein condensation, or by acting as sites of early proteolytic cleavage ...[more]

PMID: 34773861

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Project description:IntroductionAcute respiratory distress syndrome causes a heterogeneous lung injury, and without protective mechanical ventilation a secondary ventilator-induced lung injury can occur. To ventilate noncompliant lung regions, high inflation pressures are required to 'pop open' the injured alveoli. The temporal impact, however, of these elevated pressures on normal alveolar mechanics (that is, the dynamic change in alveolar size and shape during ventilation) is unknown. In the present study we found that ventilating the normal lung with high peak pressure (45 cmH(2)0) and low positive end-expiratory pressure (PEEP of 3 cmH(2)O) did not initially result in altered alveolar mechanics, but alveolar instability developed over time.MethodsAnesthetized rats underwent tracheostomy, were placed on pressure control ventilation, and underwent sternotomy. Rats were then assigned to one of three ventilation strategies: control group (n = 3, P control = 14 cmH(2)O, PEEP = 3 cmH(2)O), high pressure/low PEEP group (n = 6, P control = 45 cmH(2)O, PEEP = 3 cmH(2)O), and high pressure/high PEEP group (n = 5, P control = 45 cmH(2)O, PEEP = 10 cmH(2)O). In vivo microscopic footage of subpleural alveolar stability (that is, recruitment/derecruitment) was taken at baseline and than every 15 minutes for 90 minutes following ventilator adjustments. Alveolar recruitment/derecruitment was determined by measuring the area of individual alveoli at peak inspiration (I) and end expiration (E) by computer image analysis. Alveolar recruitment/derecruitment was quantified by the percentage change in alveolar area during tidal ventilation (%I - E Delta).ResultsAlveoli were stable in the control group for the entire experiment (low %I - E Delta). Alveoli in the high pressure/low PEEP group were initially stable (low %I - E Delta), but with time alveolar recruitment/derecruitment developed. The development of alveolar instability in the high pressure/low PEEP group was associated with histologic lung injury.ConclusionA large change in lung volume with each breath will, in time, lead to unstable alveoli and pulmonary damage. Reducing the change in lung volume by increasing the PEEP, even with high inflation pressure, prevents alveolar instability and reduces injury. We speculate that ventilation with large changes in lung volume over time results in surfactant deactivation, which leads to alveolar instability.

Dataset Information

Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.

Publications

Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.

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